Process of preparation of 16beta-methyl-9alpha-fluoro-steroids

ABSTRACT

PROCESS FOR PREPARING BETAMETHASONE AND ITS 21-ESTER DERIVATIVES BY SIMULTANEOUSLY 11B-HYDROXYLATING AND 9BROMINATING 16B-METHYL-17A-HYDROXY-1,4,9(11)-PREGNATRIENE-3,20-DIONE, DEHYDROBROMINATING THE RESULTANT 16-BMETHYL-9A-BROMO-11B,1A-DIHYDROXY-14-PREGNADIENE3,20-DIONE IN AN ALKALI MEDIUM TO OBTAIN THE 9,11EPOXY COMPOUND,FLUORINATING THE EPOXY COMPOUND TO YIELD 16B-METHYL-9AFLUORO-11B,17A-DIHYDROXY-1,4-PREGNADIENE-3,20-DIONE, DIIODINATING THE LATTER COMPOUND AT THE 21-POSITION, ACYLATING THE 21-DIIDO COMPOUND TO PRODUCE THE 21-ACYLATE, AND HYDROLYZING THE ACYLATE.

United States Patent Office 3,792,046 PROCESS OF PREPARATION OF16,3-METI-IYL- 9a-FLUOR0-STEROIDS Ivan Villax, 3 Travessa do Ferreiro,Lisbon, Portugal No Drawing. Filed Aug. 7, 1972, Ser. No. 278,394 Claimspriority, applicatgonzPortugal, Dec. 13, 1969,

5 ,9 3 Int. Cl. C07c 173/00 U.S. Cl. 260-239.55 R 9 Claims ABSTRACT OFTHE DISCLOSURE This application is a continuation-in-part of Ser. No.98,202, filed Dec. 14, 1970, now abandoned.

Since the 16fl-methyl corticosteroids are today, both pharmacologicallyand clinically the most active corticosteroids, their preparation,especially that of the fluorinated steroids is of primary importance.The most relevant compounds of this latter group are16B-methyl-9'afluoro-11,B,17a,21-trihydroxy 1,4 pregnadiene-3,20- dione(betamethasone) and its derivatives esterified at the 21-position(referred to as C21-). Betamethasone is recognized as anantiinflammatory and antiallergic agent. The ZI-esterified products ofbetamethasone are useful for the same purpose and can be administered inthe same manner and dosage as is betamethasone.

Betamethasone was first described by Taub et al. (Journ. Am. Chem. Soc.,vol. 80, p. 4435, 1958) and in a detailed manner (ibid vol. 82, p. 4012,1962), and by -Oliveto et al. (ibid vol. 80, p. 6688, 1958). PortuguesePat. No. 36,478 of Dec. 19, 1959 of the present inventor describes aprocess for preparing betamethasone. U.S. Pat. Nos. 3,053,865 (1962) ofTaub et al., 3,104,246 (1963) of Amiard et al. and 3,164,618 (1964) ofRausser et al., and the publication of R. Rausser et a1. (Journ. Org.Chem, vol. 31, p. 26, 1966) also described different processes forpreparing betamethasone and its intermediates.

Considering the various technical difliculties and the great number ofreactions involved in the above-mentioned processes, it was foundessential to join all efforts with a view to discovering a shorter ormore economical procedure by which to prepare betamethasone and itscarboxylic 2l-esters with higher intermediate and final product yields.

The present invention relates to a new method which is very economicaland provides high yields, for the preparation of the 2l-alcohol and theill-acylates of betamethasone, the intermediates III, IV and VI thereinused being novel compounds.

All processes described thus far show the introduction of the fluorineatom at C9- in the compound already hydroxylated at C21-, in view of thefact that hydroxyla- 3,792,046 Patented Feb. 12, 1974 tion of the9a-fluoro-1lp-hydroxy-steroids at C21 presents considerabledifiiculties. These difficulties have been overcome so far by using, incertain similar cases, the 21- hydroxylation by a microbiological route.This process is however, slow, expensive and of low yield.

The advantage of the present process over those previously known isbased on the following facts.

(a) The preparation of the 9(l1)-epoxy derivatives is carried out in theabsence of the hydroxyl group at C2l-, which permits to obtain almostquantitative yields (92.6% in Example 2) due to the fact that thesteroids not hydroxylated at C2lare more stable than the 21- hydroxyderivatives in an alkaline medium, which is essential for thepreparation of these epoxides.

(b) This process accomplishes, for the first time, the 21-hydroxylation,by chemical route, of the l6fl-alkyl- 9a-fluoro-1lp-hydroxy-steroidderivatives, and with a very high yield.

One of the features of the present invention is that it accomplishes,with an almost quantitative yield, the 21- hydroxylation of lfl-methyl9oz fluoro-l 15,17a-dihydroxy-1,4-pregnadiene-3,20-dione, as well as thepreparation of this latter compound.

In accordance with the present invention, a process is also provided'which atfords, in an unexpected manner, the direct diiodination of 168-methyl-9a-fluoro-11 9,17- dihydroxy-1,4-pregnadiene-3,20-dione,yielding a new compound, the 21-diiodo derivative.

The reaction of the 21-diiodo compound with a sodium or potassium saltof a carboxylic acid results in a 21- monoacylated product in spite ofthe fact that both iodine atoms at C21- are eliminated. Most surprisingis the fact that the reaction occurs likewise when the 2l-hemiacylatesof dicarboxylic acids are prepared.

A yield never attained thus far is obtained by applying the21-diiodination and subsequent deiodination sequence by means of saltsof a carboxylic acid, resulting in the introduction of the21-monohydroxy group in the form of acylates, which isperformed in theseries of the 165- al'kyl-9u-fluoro-1 l-hydroxy-steroids.

The yields of the various processes relating to hydroxylation at C21-and fluorination at C9- are compared hereafter, by way of illustration.

The process of Taub et al. in Journal of the American Chemical Society,cited above, indicates a stoichiometric yield of 77% for hydroxylationat C21- (Compounds 25 and 26) and 55.5% for fluorination until theimpure 21- acetate of betamethasone is obtained (Compounds 44, 45a, 45b,46b). The yield given in U.S. Pat. No. 3,104,246 for hydroxylation is(Example IV) and for fluorination, according to Example V, it refers tothe publication of Taub et al. (thus the yield is 55.5%). U.S. Pat. No.3,164,618 indicates a yield of 58.5% (Examples 113 and F) forhydroxylation and 15.7% (Examples 17B, 18A and B) for fluorination. Thepublication in Journal of Organic Chemistry, cited above, indicates ayield of 72.5% for hydroxylation (Compound XIIIa and b) and 55% forfluorination (Compounds XVIH, XIX, XXa, XXb). The fluorination iscarried out in the present invention with a yield of 73.1% (Examples 1,2 and 3) before introduction of the hydroxylation group at 021-, theyield of this latter compound being 86.6% (Examples 5 and 6). Thus, thestoichiometric overall yields for the two phases, until the 21-acetateof betamethasone is obtained, are as follows:

The present process relates therefore to the preparation of thecompounds of the formula where R is a hydrogen atom, an acyl group or acarboxylacyl group, and salts thereof, e.g. alkali and alkaline earthmetal salts. R is preferably limited to 2 to 28 carbon atoms, mostpreferably 2 to carbon atoms. Examples of the salts are sodium andcalcium salts.

The raw material used in the present process, 16 3-methyl-17a-hydroxy-1,4,9(11) pregnatriene-3,20-dione, has the formulaThe compound HI is then dehydrobrominated in an alkaline medium by aconventional procedure, such as treatment with an aqueous or methanolicsolution of potassium or sodium hydroxide or bicarbonate, or by means ofsodium methoxide, in an inert solvent such as methanol, ethanol,dichloroethane, chloroform or a mixture thereof, and preferably in aninert atmosphere, such as nitrogen, yielding the novel compound16/3-methyl-9,11-

epoxy-17a-hydroxy-1,4-pregnadiene 3,20 dione of the formula with almostquantitative yield. The reaction temperature is preferably from 0 to 25C., with a reaction time of 1-4 hours. The essential reason accountingfor the high yield is the lack of substitution at 021-, which rendersthe molecule much more stable in the alkaline medium where thedehydrohalogenation reaction takes place.

In the next step, Compound IV is fluorinated by a known procedure in aninert medium such as by intimate contact with a solution of anhydroushydrofluoric acid in dichloromethane, chloroform, tetrahydrofuran,dimethylformamide, or with an aqueous solution of hydrofluoric acid of aconcentration not less than 60%, at a temperature between 70 C. and 0 C.for 1-5 hours, yielding the compound 16/? methyl-9a-fluoro-118,17a-dihydroxy-l,4- pregnadiene-3,20-dione of the formula with almostquantitative yield. The reaction temperature is preferably from 24 to 28C., with a reaction time of 1-2 hours. The reaction occurs smoothlywithout any side reactions.

The acylation of Compound VI by means of alkali and alkaline earth metalsalts, e.g. potassium, calcium or sodium salts, of carboxylic acids,according to known procedures, in an inert medium, e.g. acetone, aqueousacetone, dimethylformamide, diethylformamide, acetonitrile or a mixturethereof, occurs without any difficulty, yielding the 21-acylates ofbetamethasone, such as the 21-acetate from which betamethasone can beobtained by simple hydrolysis, as known. The reaction temperature is upto the boiling point of the solvent, and preferably at the boilingpoint, with a reaction time of 2-4 hours.

Consequently, the present invention also provides a process for thepreparation of novel Compounds III, IV and VI which are usefulintermediates in steroid chemistry, in the preparation of betamethasoneand 21-acylates thereof. Among the 21-acylates, we have found the 21-nicotinate, which possesses surprising and unexpected properties ofpharmacological behaviour. It is absorbed by the skin two times moreefficiently than the 17-valerate of betamethasone, thus it representsanother feature of the present invention.

The reaction conditions and isolation of the products are largelydescribed, by way of illustration, in the following examples, whichhowever are not intended to limit the scope of the present invention.

EXAMPLE 1 69.9 g. of 1613 methyl17a-hydroxy-1,4,9(11)-pregnatriene-3,20dione--melting point 168-170 C.,

E12,, 435 at 239-240 m is added to 812 cc. tetrahydrofuran and 433.8 cc.diluted perchloric acid (27.6 cc. 70% perchloric acid diluted with waterto make 1000 no). The reaction mixture is cooled to +15 C. and. 36.99 g.N-bromoacetamide is added, causing an increase in the temperature ofabout 5 C. It is then stirred for 4 hours at a temperature of 25 30 C.The reaction mixture is quenched by addition of a few drops of anaqueous solution of sodium bisulfite. The desired 16;? methyl 9abromo-l1B,17a-dihydroxy-1,4- pregnadiene-3,20-dione, a novel product,precipitates by addition of the reaction mixture to 4 litres of waterand ice. The crude product, when washed with water and dried at 40 C.,weighs 85.8 g., having a melting point of 157 158 C., specific rotation[a] +120 (c.=1 in dioxane),

value being 308 at 243 mu in methanol. The product is soluble indioxane, slightly soluble in ethyl acetate and insoluble in ether andwater, the principal peaks of the infrared absorption curve being at2.9,, 5.84 6.02 6.16;, 9.6% 9.98;; and 11.3,u.

Analysis. C 'H O- Br=437.4. Calculated: Br, 18.26%. Found: Br, 18.37%.

EXAMPLE 2 85.3 g. of the crude product obtained in the previous exampleis suspended in 1.011 litres methanol, 674.3 cc. chloroform is added,followed by the dropwise addition of 200.28 cc. of a normal solution ofsodium hydroxide, during 25 minutes, under stirring and nitrogenatmosphere at a temperature between 0 and +3 C. After stirring for 3hours, the reaction mixture is neutralized with 50% aqueous acetic acidand concentrated under vacuum until a crystalline slurry is obtained.The product is then precipitated by addition of 1.390 cc. of water andice, yielding 64.4 g. of the desired new product16/3-methyl-9',11-epoxy- 17a hydroxy 1,4 pregnadiene-3,20-dione, whichhas a melting point of 186191 C., specific rotation [a] +50(C.=1i11dioxane),

EXAMPLE 3 52 g. of the product obtained in the previous example is addedin small fractions, during 20 minutes, to 365 cc.

hydrofluoric acid diluted with dimethylforma-mide (60%) and cooled to 20C. The reaction mixture is stirred during 3.5 hours at 16" to 1 8 C. andis poured into a mixture of 4.8 kg. of ice, 960 cc. of water and 921 cc.of concentrated ammonia. The product is filtered, washed several timeswith water until it contains no inorganic salts, and then dried,yielding 56.5 g. of the desired product 16,8 methyl 9m fluoro 115,17dihydroxy-1,4- pregnadiene-3,20-dione in an impure state. The product,thus obtained, is pulverized and recrystallized from chloroform,yielding the product in the form of a chloroform solvate. The chloroformof crystallization is eliminated by heating to 105 C., yielding 44.3 g.of the product. Yield: 82.4%. The final product has a melting point of230- 234 C., specific rotation [0t]n+100i10 (c.=1 in dioxane),

at 239 m It is moderately soluble in methanol, slightly soluble indichloromethane and chloroform and insoluble in ethyl and isopropylether and water. The principal peaks of the infrared absorption curve inmineral oil mull are at 2.9844, 5.82 6.01 6.16 6.21,u, 10.13 1043 and11.1,u. This curve differs substantially from that of the solvate.

Analysis.-C H O F=376.45. Calculated: C, 70.18%; H, 7.76%; F, 5.05.Found: C, 70.2%; H, 7.81%; F, 4.91%.

EXAMPLE 4 The procedure of the previous example is followed, but insteadof a 60% solution of hydrofluoric acid in dimethylformamide, aqueoushydrofluoric acid is used. The final yield is 43.4 g. of productidentical to that obtained in Example 3.

EXAMPLE 5 14 g. of the product obtained in Example 4 is added to amixture of 56 cc. absolute methanol and 14 cc. of a 10% methanolicsolution of anhydrous calcium chloride, the reaction temperature beingbetween +25 and +27 C. After stirring for 5 minutes, 7 g. calcium oxidepowder is added, and stirring continued for 25 minutes more. It is thenadded to a solution containing 18.8 g. resublimed iodine in 42 cc. of a10% methanolic solution of anhydrous calcium chloride and 28 cc.absolute methanol, under nitrogen atmosphere in the dark, at atemperature between 25 -27 C., the addition speed being set according tothe discoloration of the solution added. It is stirred for 15 minutesmore, cooled to 10 to 12 C., and stirring is continued for half an hourat that temperature. The product is then precipitated by addition of1500 cc. of water and ice containing 15 cc. acetic acid. It is stirredfor 1 hour, the precipitate is filtered, washed and dried under vacuum.The yield of the desired new product 16,8-rnethyl 9oz fluoro 113,170;dihydroxy-Zl,21-diiodo-1,4- pregnadiene-3,20-dione is 20.6 g., having ahumidity content of 4.9%. Yield: After washing with methanol, theproduct has a melting point of 164-166 C. with decomposition. Theinfrared absorption curve in mineral oil shows principal peaks at 2.9,u,5.85;, 6:0'Lu, 6.18 6.22,u., 82611., 9.37 t, 9.5,u, 11.111. and 1122p.

EXAMPLE 6 9.2 g. of the product of the previous example is added to amixture of 91.08 cc. acetone, 0.92 cc. water, 0.92 cc. acetic acid and9.2 g. anhydrous potassium acetate. It is refluxed for 1 hour and 30minutes in the dark under nitrogen atmosphere. It is cooled to 55 C.,and after stirring for 5 minutes it is precipitated by addition of 730cc. water and ice, yielding 6.2 g. of the desired betamethasone acetate.Yield: 86.6%. Recrystallization from acetone yields the pure product,having a melting point of 2l8-220 C., specific rotation [a] (c.=1 indioxane),

7 EXAMPLE 7 67 g. of the product prepared according to Example 6 isadded to 250 cc. methanol, followed by addition of 45 cc. 2 N methanolicsodium methoxide. After minutes, a. further amount of 18 cc. 2 N sodiummethoxide is added, and at the end of 20 minutes it is neutralized with50% aqueous acetic acid. After precipitating with water, 57.1 g.betamethasone is obtained. Yield: 96.4%. After recrystallizing fromethyl acetate, the melting point is 232-234 C., whereas whenrecrystallizing from acetone it melts at 245 C. The product so obtainedis identical to that described in the literature.

EXAMPLE 8 By substituting the potassium acetate of Example 6 bypotassium-valerate, -isovalerate, -palmitate, in a mole/ mole equivalentamount, and repeating the reaction described in Example 6, therespective 21-valerate, 21- isovalerate and 21-palmitate ofbetamethasone are obtained.

EXAMPLE 9 By repeating Example 6, but using the monopotassium salt ofsuccinic acid, and adjusting the pH of the reaction mixture to 6.0 withtriethylamine, the ZI-hemisuccinate of betamethasone is obtained, whichyields, after isolation and neutralization of the free carboxylic groupwith sodium hydroxide, the 21-hemisuccinate of betamethansone in thefoam of a sodium salt.

EXAMPLE 10 By repeating Example 6, but using 9.2 g. anhydrous potassiumnicotinate instead of potassium acetate, betamethasone ZI-nicotinate isobtained with a yield of 81.2%. Subsequently, an ointment is preparedwith the product thus obtained:

Percent 'w./w. Betamethasone 21-nicotinate 0.1 Liquid parafiin 10 Whitsoft parafiin as to prepare 100 parts by weight.

The active ingredient is mixed with one third of the amount of liquidparaffin in a porcelain ball-mill and milled until the particle size isreduced for an average of 3-4p.. The paste thus obtained is diluted andwashed out with the remaining liquid parafiin and incorporated into thesoft paraffin previously liquified by heating to 55 C. in a water-bath.Subsequently, it is let to cool down slowly, under stirring, to achievehomogenicity of the onitment. This ointment has been compared with anointment of the same composition containing betamethasone 17-valerate ofthe same concentration. In the kaolin foot edema test in rats (12 ineach group), the absorption of the betamethasone 21-nicotinate was inaverage 1.87 times faster than that of the valerate.

I claim:

1. A process for preparing a compound of the formula 3,20-dione in aninert solvent by reaction with N- bromosuccinimide or N-bromoacetamidein the presence of aqueous perchloric acid to obtain l6 3-methyl 9abromo 11,63,170; dihydroxy 1,4 pregnadiene-3,20-dione,

(b) dehydrobrominating the product of step (a) by reacting the productwith an alkaline substance selected from the group consisting ofpotassium hydroxide, sodium hydroxide, potassium bicarbonate, sodiumbicarbonate and sodium methoxide in an inert solvent to otbain l63-methyl9,l1-epoxy-17ahydroxy-1,4-pregnadiene-3,20-di0ne,

(c) fiuorinating the product of step (b) by reacting the product withhydrofluoric acid in an inert solvent to obtainl6B-methy1-9a-fluoro-11p,17a-dihydroxy- 1,4-pregnadiene-3,20-dione,

(d) diiodinating the product of step (c) by reacting the product withelemental iodine in an inert solvent in the presence of calcium oxide toobtain 16B methyl 9oz fluoro 115,170; dihydroxy-21,2l-diiodo-1,4-pregnadiene-3,20-dione,

(e) acylating the product of step (d) in an inert solvent with an alkalior alkaline earth metal salt of a carboxylic acid selected from thegroup consisting of monocarboxylic acids of 2-16 carbon atoms, succinicacid and nicotinic acid, and

(f) hydrolyzing the product of step (e) to obtain the compound ofFormula I wherein R is hydrogen.

2. The process according to claim 1, wherein the inert solvents areselected from the group consisting of dioxane and tetrahydrofuran instep (a), methanol, ethanol, dichloromethane, chloroform and a mixturethereof in step (b), dichloromethane, chloroform, tetrahydrofuran,dimethylformamide, diethylformamide and water in the form of aqueoushydrofluoric acid having a concentration of at least 60% in step (c),methanol and a methanolic solution of calcium chloride in step (d) andacetone, dimethylformamide, diethylformamide, acetonitrile and a mixturethereof in step (e).

3. The process according to claim 1, wherein the reaction temperaturesare 15 to 35 C. in step (a), 0 to 25 C. in step (b), --70 to 0 C. instep (c), 24 to 28 C. in step (d) and the boiling point of the solventin step (e).

4. The process according to claim 1, wherein the reaction times are 1-6hours in step (a), 1-4 hours in step (b), 1-5 hours in step (c), 1-2hours in step (d) and 24 hours in step (e).

5. The process according to claim 1, 'wherein the salt used in step (e)is a potassium salt.

6. The process according to claim 1, wherein R is selected from thegroup consisting of acetyl, valeryl, isovaleryl, palmityl and nicotinyl.

7. The process according to claim 1, wherein step (e) is carried out atthe reflux temperature of the reaction mixture and step (t) is carriedout in a methanolic solution of sodium methoxide.

8. 16fi-methyl 9,11 epoxy 17a hydroxy-l,4-pregnadiene-3,20-dione.

9. 16,3 methyl 9a fluoro 116,170: dihydroxy-21,2l-diiodo-1,4-pregnadiene-3,20-dione.

References Cited UNITED STATES PATENTS 3,104,245 9/ 1963 Joly et al.260-397.45 3,119,815 1/1964 Amiard et al 260-23955 3,173,837 3/1965 VonWerder et al. 167-77 3,374,230 3/1968 Gardner et al. 260-23955 3,375,2613/ 1968 Arth et al. 260-397.45

HENRY A. FRENCH, Primary Examiner U.S. Cl. X.-R.

1613-methyl 17a hydroxy-1,4,9(1l)-pregnatriene- 260-2395, 397.45

